Screening for : Evaluating the Evidence THOMAS J. GATES, M.D., Lancaster General Hospital, Lancaster, Pennsylvania

Many patients expect to undergo screening tests for cancer. In evaluating screening procedures, physicians must take into account the known effects of lead time, length and screening biases, all of which can result in an overestimation of the benefits of screening. The gold standard by which a screening test is evaluated remains the prospective, randomized controlled trial, demonstrating reduced morbidity and mor- tality. The magnitude of benefit from screening is best expressed in terms of the num- ber of patients needed to screen. This value ranges from approximately 500 to 1,100 for proven screening interventions. These concepts are illustrated by controversies in current screening recommendations for of the cervix, lung, colon, breast and prostate, which together account for more than 50 percent of cancer deaths in the United States. (Am Fam Physician 2001;63:513-22.)

atients frequently consult family screening is to reduce morbidity and mortal- physicians with the expectation ity. If improved outcomes cannot be demon- of undergoing screening tests for strated, the rationale for screening is lost. Early cancer. However, controversy diagnosis by itself does not justify a screening remains as to which screening program. The only justification for a screening Pprocedures are justified and how proposed program is early diagnosis that leads to a mea- screening procedures should be evaluated. surable improvement in outcome. Failure to understand basic concepts can lead to unrealistic expectations for screening ETHICAL ISSUES programs and sometimes to inefficient use Although screening is unquestionably im- of resources. This article reviews the kind of portant, other issues of equal importance in- evidence required to justify screening tests clude using scarce resources efficiently and for cancer, with the goal of guiding family rationally, refraining from unproven or inef- physicians through current and future fective interventions and doing no harm. In screening controversies. fact, sometimes there are good reasons not to screen. Basic to this is the understanding that Key Issues Involving Screening the proposal to screen an asymptomatic Screening can be defined as the application patient involves a fundamental shift in the of diagnostic tests or procedures to asympto- physician-patient relationship. matic people for the purpose of dividing them In ordinary medical practice, the patient into two groups: those who have a condition initiates an encounter because of a troubling that would benefit from early intervention symptom. The physician pledges to help but and those who do not.1 The importance of can make no guarantee and is not responsible screening is deeply embedded in primary care: if the symptom turns out to represent some- family physicians believe in the value of thing beyond the ability of current medical detecting disease at an early, asymptomatic practice to cure. By contrast, a screening test is stage when it is more likely to be amenable to usually initiated by the physician (or indi- treatment and cure. However, it is important rectly, by professional or advocacy groups) to recognize that the ultimate purpose of and, in this situation, there is an “implied promise” not just that the screening procedure See editorial on page 440. might be beneficial, but that it is in fact bene- ficial, that it will do more good than harm.2,3

FEBRUARY 1, 2001 / VOLUME 63, NUMBER 3 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 513 be harmful, by providing false reassurance Early diagnosis alone does not justify a screening program. and thereby encouraging patients to neglect important symptoms. Finally, a screening test The only justification is early diagnosis that leads to a may correctly diagnose a disease but, if the measurable improvement in outcome. resulting therapy is ineffective or harmful, the patient has been harmed rather than helped.3 In light of these considerations, justification These considerations add an often neglected of screening tests requires a more rigorous ethical dimension to screening.2,4,5 standard of evidence than is usually applied in ordinary clinical practice. Table 1 defines the THE IMPACT OF FALSE-POSITIVE characteristics of an ideal screening test. AND FALSE-NEGATIVE TESTS Even if the benefits of a screening test have Bias in the Evaluation been proved, the benefits accrue to only a few of Screening Tests persons. By contrast, all persons participating The evaluation of screening tests is compli- in a screening program are at risk for harm.2 cated by certain biases that occur when a dis- Over and above the cost and discomfort of the ease is diagnosed by screening in the asymp- actual test, the most important potential harm tomatic period. The nature of these biases is is the risk of a false-positive result. Because such that “early diagnosis will always appear diseases being screened for have a low preva- to improve survival, even when the therapy is lence, even the best screening test will have a worthless.”3 low positive predictive value (often 10 to 20 percent). Thus, most positive results will be FEASIBILITY OF SCREENING false-positive, leading to further work-up and Figure 13 shows how the “critical point” in patient anxiety. False-negative results can also the natural history of a disease determines the feasibility of screening. The disease pro- gresses from its biologic onset at the cellular level (e.g., a mutation) and through an TABLE 1 asymptomatic period when it is theoretically Characteristics of the Ideal Screening Program detectable by a screening test, eventually cul- minating in the onset of symptoms, when the Features of the disease diagnosis can be made by the usual clinical Significant impact on public means. The critical point can be defined as Asymptomatic period during which detection is possible that point in the natural history of the dis- Outcomes improved by treatment during asymptomatic period ease before which therapy is relatively effec- Features of the test tive and after which therapy is relatively inef- Sufficiently sensitive to detect disease during asymptomatic period fective. In the case of cancer, the critical point Sufficiently specific to minimize false-positive test results would represent the time at which regional Acceptable to patients or distant metastasis occurs. Features of the screened population Whether a screening test is effective depends Sufficiently high prevalence of the disease to justify screening on whether the critical point occurs before, Relevant medical care is accessible Patients willing to comply with further work-up and treatment during or after the asymptomatic period. If the critical point occurs early, as in lung cancer, Adapted with permission from Mulley AG. Health maintenance and the role of screening will not be effective because the dis- screening. In: Goroll AH, May LA, Mulley AG. Primary care medicine. 3d ed. ease will have “escaped from cure”before it was Philadelphia: Lippincott, 1995:13-6. detectable by screening. If the critical point is late, as in endometrial cancer, screening is

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The rightsholder did not grant rights to reproduce this item in electronic media. For the missing item, see the original print version of this publication.

FIGURE 1.

unnecessary because the disease is curable nosis to death will be three years. However, in even when it presents with clinical symptoms. a screened population, the diagnosis will be Screening will have a potential effect on the made in the asymptomatic period, an average natural history of the disease only when the of two years before clinical symptoms occur. critical point occurs sometime during the The time from diagnosis to death will now be asymptomatic period, as in . five years (two years in the asymptomatic period plus three years in the clinical period). SCREENING BIAS Screening bias (a type of ) occurs because subjects who volunteer for Lead-Time Bias screening (or, in randomized trials, those who comply with screening recommendations) Natural history 4 years Diagnosis 3 years tend to be healthier than those who do not Onset at clinical Death volunteer or do not comply, with lower rates Asymptomatic period presentation Clinical illness of mortality not just from the disease in ques- tion but from all causes. Thus, an observed Unscreened population benefit may be due not to the screening inter- Diagnosis based 3 years on clinical Death vention but only to the self-selection of a presentation 3 healthy cohort of volunteers. Median time from diagnosis until death: 3 years

LEAD-TIME BIAS Screened population 2 years 3 years Figure 2 illustrates the important concept Clinical symptoms Death of lead-time bias, which is best explained schematically. Lead-time bias occurs when the asymptomatic period in the natural his- Screening diagnosis 5 years Death tory of the disease is not taken into account. Median time from diagnosis until death: 5 years For example, assume a hypothetic disease that is 100 percent fatal, with an average survival rate of three years from the time of clinical FIGURE 2. Schematic representation of lead-time bias. Assuming a fatal presentation and a preceding asymptomatic disease with an average survival of three years from the time of clinical presentation, the screened population will seem to have better out- period of four years. In an unscreened popu- comes in terms of median survival. However, these patients are not actu- lation, the diagnosis will be based on clinical ally living longer than the unscreened population but are merely finding symptoms, and the median time from diag- out about their disease at an earlier point in the natural history.

FEBRUARY 1, 2001 / VOLUME 63, NUMBER 3 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 515 vival are sensitive to the elapsed time from In screening for a disease with a low prevalence, most diagnosis until death and will therefore be positive test results will be false-positives. skewed by a screening program.

LENGTH BIAS Length, or length-time, bias (Figure 3) When the two populations are compared in occurs because of the heterogeneity of disease, terms of median survival (or five-year sur- which presents across a broad spectrum of vival), the screened population will appear to biologic activity. In the case of cancer, some have better outcomes even without therapy. patients will have fast-growing, aggressive However, as can be seen in Figure 2, the tumors with short asymptomatic periods and screened patients are not actually living rapid progression from symptoms to death. longer but only finding out about their dis- Other patients will have slower-growing, less ease at an earlier point in its natural history. aggressive tumors that are less likely to metas- Screening has given them not an extra two tasize and, therefore, have a better prognosis. years “forward” of life but an extra two years These less aggressive tumors have a longer “backward” of disease.3 asymptomatic period and are therefore more In studies of screening efficacy, the only way likely to be identified in a screening program. to avoid lead-time bias is to compare actual In the hypothetical example portrayed in mortality rates in the screened and unscreened Figure 3, with a screening interval of one year, populations. Mortality rates are not influenced aggressive tumors have at most a 50 percent by the timing of diagnosis, whereas surrogate chance of being diagnosed by screening (the measures like median survival or five-year sur- other 50 percent progressing from onset through the asymptomatic period to clinical symptoms in the interval between screening examinations). By contrast, less aggressive Length Bias tumors have a long asymptomatic period and are therefore almost certain to be found on Aggressive disease annual screening. When a cohort identified by 6-month asymptomatic 1 year of screening (e.g., ) is compared period Clinical symptoms Onset Death with a cohort identified by clinical presenta- presentation tion (e.g., palpable mass), less aggressive tumors will be overrepresented in the screen- Screening interval: ing cohort, and more aggressive tumors will 1 year be overrepresented in the clinical presentation cohort. Even in the absence of therapy, the cohort identified by screening will have a bet- Onset Clinical Death 2-year asymptomatic periodpresentation 4 years of ter prognosis. A screening program may symptoms Less aggressive disease appear to improve survival when in fact it has only preferentially selected out the subgroup with the best prognosis.3 FIGURE 3. Schematic representation of length (or length-time) bias. In the case of cancer, patients with aggressive tumors have at most a 50 Evaluation of Screening Tests percent change of diagnosis on annual screening. By contrast, less Because of the complex and unpredictable aggressive tumors, with long asymptomatic periods, will almost cer- tainly be detected on annual screening. Thus, a screening program can nature of these various biases, the only reli- appear to improve survival when it has only selected outpatients with able way to prove the effectiveness of a pro- the best prognosis. posed screening program is to demonstrate

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TABLE 2 Because of lead time and length bias, early diagnosis will Measures of Screening Effectiveness always appear to improve survival, even when therapy is ineffective. Relative risk and relative risk reduction Gain in life expectancy7 Cost per case detected Cost per life saved rates specific evidence guidelines and remains Gain in quality-adjusted life years (QALYs) the most authoritative source for screening rec- 8 Number needed to screen (NNS) ommendations. Table 3 summarizes the Task Force’s rating system. The Task Force has recently reconvened and will offer revised rec- lower rates of all-cause or disease-specific ommendations on cancer screening beginning mortality in a randomly assigned screened in 2001. These revisions will be published as population compared with unscreened con- they become individually available on the Web trol subjects, using intention-to-treat analy- site of the Agency for Healthcare Research and sis,3 a so-called “randomized controlled trial.” Quality (AHRQ, formerly Agency for Health Some screening interventions have fulfilled Care Policy and Research [AHCPR]) at www. this high standard. Those that have not ahrq.gov/clinic/cpgsix/htm. A personal com- should be considered experimental, with munication from David Atkins, M.D., M.P.H., unproven benefits, and patients should give Coordinator for Clinical Preventive Services, informed consent before participating.2,4 AHRQ, indicates that the new recommenda- Even when screening tests have fulfilled this tions will take into account cost/benefit consid- high standard of evidence, the manner in erations, as well as evidence of medical efficacy. which results are reported can influence our perception of the magnitude of the benefit.6 Table 2 summarizes various ways in which TABLE 3 benefits of screening have been reported.7,8 Summary of USPSTF Ratings of Strength This article will rely on the number needed to of Recommendations and Quality of Evidence screen (NNS), which is calculated simply as the reciprocal of the absolute risk reduction Strength of recommendation (NNS = 1/ARR).8,9 The NNS represents the A. Good evidence to support number of patients who must be enrolled in a B. Fair evidence to support C. Insufficient evidence to recommend for or against screening program over a given period of time D. Fair evidence against (here normalized to 10 years) to prevent one E. Good evidence against death from the disease in question. (The num- Quality of evidence ber of screening tests that would be required to I. Evidence from at least one randomized controlled trial prevent one death would be up to 10 times II-1. Evidence from controlled trials without randomization higher, depending on the frequency of screen- II-2. Evidence from cohort or case-control studies ing.) The NNS reflects both the prevalence of II-3. Evidence from multiple time series or historic controls the disease and the effectiveness of therapy, III. Expert opinion based on clinical experience and has the advantage of being easy to calcu- late and intuitively useful to clinicians and USPSTF = U.S. Preventive Services Task Froce. patients. It does not, however, specifically Adapted from U.S. Preventive Services Task Force. Guide to clinical preventive account for the risks or the costs of screening. services: report of the U.S. Preventive Services Task Force. 2d ed. Baltimore: The U.S. Preventive Services Task Force Williams & Wilkins, 1996. Guide to Clinical Preventive Services10 incorpo-

FEBRUARY 1, 2001 / VOLUME 63, NUMBER 3 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 517 to demonstrate its effectiveness,10 historical The number needed to screen (NNS) represents the number data from British Columbia document an 80 of patients that would have to be enrolled in a screening percent decrease in mortality caused by cervi- cal cancer between 1955 and 1988.11 Using program to prevent one death. the absolute risk reduction from this data, we can calculate an NNS of 1,140, meaning that 1,140 women would have to be regularly Current Controversies screened over 10 years to prevent one death in Cancer Screening from cervical cancer. An appreciation of these concepts can help Current controversies in screening for cer- us understand many of the current contro- vical cancer include the proper interval for versies in cancer screening. The discussion Pap smears10,12 and the role of new technolo- that follows is not meant to be comprehensive gies that may increase sensitivity but at a high but simply to illustrate the importance of marginal cost. At present, no reliable data exist these considerations in evaluating the evi- with which to resolve these controversies. dence for screening. The following informa- tion highlights controversies involving five LUNG CANCER types of cancer (Table 4) that together By contrast, screening for lung cancer with account for more than 50 percent of cancer chest , sputum cytology, or both, deaths in the United States. is the paradigm of an ineffective screening program. Although most physicians are aware CERVICAL CANCER that these tests are no longer indicated for Papanicolaou smear screening for , many are not aware of the history cancer represents the prototype of a success- of screening for lung cancer.13 Various propos- ful cancer screening program. Although there als to screen smokers for lung cancer were has never been a randomized controlled trial made throughout the 1950s, and by 1959 pub- lished reports documented a shift to earlier- stage disease and improved five-year survival rates in patients diagnosed by screening, com- TABLE 4 pared with those diagnosed clinically. Screen- Annual Mortality Associated with Selected Types ing smokers by annual chest roentgenograms of Cancer in the United States was subsequently endorsed by the American Cancer Society (ACS), but eventually three Number Percentage* Numerical rank large, randomized controlled trials docu- of deaths of total cancer as cause of Type of cancer per year deaths per year cancer deaths mented no reduction in mortality in the screened population, and the ACS rescinded Lung 160,100 28.0 1 (overall) its recommendation in 1980. Colorectal 56,500 10.0 2 (overall) The main lesson in this is that lead-time Breast 43,900 7.7 2 (in women) and length biases are not just theoretical; they Prostate 39,200 6.9 2 (in men) confound our ability to evaluate screening Cervical 4,900 0.9 9 (in women) programs. Furthermore, in the case of lung cancer, the false promise of early detection by *—Percentage of 565,000 U.S. cancer deaths annually. (The four most common screening detracted from the real solution, cancers account for > 51 percent of total cancer deaths in the United States.) which is prevention of illness and death Adapted with permission from Landi SH, Murray T, Bolden S, Wingo PA. Cancer through cessation of tobacco use. statistics, 1998. CA Cancer J Clin 1998;48:6-29. Recently, investigators have shown that with the use of spiral computed tomographic

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(CT) scanning in asymptomatic smokers, it is possible to detect small, potentially resectable The USPSTF Guide to Clinical Preventive Services incorpo- lung cancers with greater sensitivity and at an rates specific evidence-based screening guidelines. The earlier stage than with conventional chest roentgenograms.14 As yet, no data suggest that guidelines are available online at CT screening decreases mortality, but it appears likely that the debate over screening for lung cancer may soon be reopened. that none of the three studies was able to demonstrate a reduction in overall mortality but only in disease-specific mortality. This Three randomized controlled trials have finding raises the possibility that, in return for documented a reduction in colorectal cancer such a large investment of society’s resources, mortality in populations screened with fecal colon cancer screening programs may not occult blood testing. The first study15 used actually save lives but only shift patients to volunteers, and rehydration of slides resulted competing causes of mortality. in a very high colonoscopy rate, with a 33 per- cent reduction in relative risk of death from colorectal cancer. Two subsequent studies16,17 Several randomized controlled trials have were community-based and did not use rehy- demonstrated a reduction in breast cancer dration, demonstrating more modest relative mortality in cohorts screened by annual or reductions in mortality associated with col- biannual mammography, making mammog- orectal cancer of 15 and 18 percent. The raphy one of the best-documented screening absolute risk reduction from the latter two procedures. However, considerable contro- studies gives an NNS of 1,00016 and 588.17 versy remains about the age at which screen- Even though the relative reduction in mortal- ing should be initiated. ity associated with screening is only 15 to 18 A meta-analysis of eight randomized con- percent (compared with 80 percent for Pap trolled trials of women 50 to 74 years of age smears), the NNS compares favorably with shows a relative risk of breast cancer mortal- that of cervical cancer screening because ity in the screened group of 0.77.22 Using this deaths from colorectal cancer are much more data as well as the background of common than those from cervical cancer. breast cancer, one can estimate an NNS of Controversy remains over the role of sig- 543, which represents the number of women moidoscopy in screening for colorectal cancer. who would have to be enrolled in an ongoing Screening is supported by case-control stud- screening program over 10 years to expect to ies18 but no randomized controlled trials. Two save one life from otherwise-fatal breast can- recent trials have demonstrated that in asymp- cer. By contrast, the same meta-analysis tomatic patients found to have advanced prox- showed that in women 40 to 49 years of age imal neoplasms on colonoscopy, more than the relative risk in the screened group was not one half had no distal abnormalities and, thus, significant (0.92), giving an NNS of 3,125 in would have been missed on sigmoidoscopic this younger cohort. Calculations based on screening.19,20 This finding would suggest that gains in life expectancy7 and cost per year of colonoscopy would have a significantly higher life saved23 also show that screening in the yield than sigmoidoscopy but, of course, at a younger age group is about five times more higher overall cost. expensive than screening in the over-50 Another controversy is the high cost of col- group and only one fifth as effective. orectal cancer screening (about $300,000 per A 1997 National Institute of Health consen- death prevented),21 combined with the fact sus conference concluded that current data

FEBRUARY 1, 2001 / VOLUME 63, NUMBER 3 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 519 did not warrant routine screening mammog- American Family Physician.27 The introduc- raphy in women 40 to 49 years of age and rec- tion of the PSA test in 1986 was initially fol- ommended that decisions be individualized lowed by a dramatic increase in the incidence on the basis of the patient’s risk factors and of and a fourfold increase in preferences. This recommendation resulted in the rate of radical prostatectomy.28 A decline a firestorm of protest, culminating in a U.S. in incidence has been noted during the past Senate vote (98 to zero) that endorsed univer- few years, presumably because the initial sal screening for women 40 to 49 years of backlog of undiagnosed asymptomatic tu- age.24 In view of this highly politicized envi- mors has been eliminated by widespread PSA ronment, it seems prudent to offer screening screening. mammography to women in this age group, By contrast, mortality rates from prostate but only after a discussion of the limited ben- cancer have been fairly constant, increasing efits and the high cumulative rate of false-pos- by 1 percent per year until 1992 and declining itive results, which can approach 50 percent by about 1 percent per year starting in 1993.29 after 10 annual mammograms.25 There has also been a documented shift to The status of screening mammography has earlier-stage disease and an increase in five- been further questioned by the recent publi- year survival rates.30 Because prostate cancer cation of a new meta-analysis of the same is often slow-growing with a long asympto- eight trials. These authors argue that six of the matic period, these results are almost cer- eight trials in the original meta-analysis show tainly affected by lead-time and length bias, evidence of inadequate or flawed randomiza- and some have maintained that the current tion and allocation. When these six trials are situation is exactly analogous to the situation eliminated, the remaining two adequately with screening programs for lung cancer.13,30 randomized trials show no effect of screening In the absence of randomized controlled on breast cancer mortality.26 Although most trials, PSA screening remains an unproven commentators have not accepted the authors’ intervention, and it is therefore impossible to conclusion that “screening for breast cancer calculate measures of screening effectiveness with mammography is unjustified,”26 it does such as NNS. Randomized controlled trials underscore the fact that the evidence sup- are under way in the United States and porting screening mammography remains Europe, but results will not be available for controversial. several years. In the meantime, the American College of Physicians and the American Acad- PROSTATE CANCER emy of Family Physicians recommend that Screening for prostate cancer with the men older than 50 years be counseled about prostate-specific antigen (PSA) test is perhaps the “known risks and unknown benefits” of the most controversial issue in cancer screen- PSA screening, and that informed consent be ing. This subject was recently reviewed in obtained from those who wish to proceed with screening.

Final Comment The Author Because patients often expect to undergo THOMAS J. GATES, M.D., is associate director of the family practice residency at Lan- screening tests for cancer, physicians must caster General Hospital, Lancaster, Pa. He received his medical degree from Harvard know how to evaluate the evidence in sup- Medical School, Boston, and served a residency in family practice at the University of Utah School of Medicine, Salt Lake City. port of screening and how to convey that evi- dence to patients in an understandable way. Address correspondence to Thomas J. Gates, M.D., Department of Family and Com- munity Medicine, Lancaster General Hospital, 555 N. Duke St., Lancaster, PA 17604 In an era when advocacy groups and subspe- (e-mail: [email protected]). Reprints are not available from the author. cialty organizations have taken the lead in

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TABLE 5 Summary of Cancer Screening Tests

Strength of Quality of Test recommendation* evidence* RRR† NNS‡ Controversies

Pap smear for A II-2, II-3 > 0.80 1,140 Interval, new cervical cancer technologies, when to stop Mammography Age >50 years A I, II-2 0.23 543 Interval (annual vs. biannual), when to stop Age 40 to 49 C I 0.08 3,125 Some evidence of years significant reduction with follow-up >10 years; false-positives FOBT for colorectal B I 0.15-0.20 588-1,000 Interval (annual vs. cancer biannual), compliance, role of sigmoidoscopy, cost/benefit PSA for prostate D II-2 NA NA Unproven; RCTs in cancer progress Chest film for D I, II-1 NA NA Recent reports of spiral lung cancer CT for screening may reopen controversy

Pap = Papanicolaou; FOBT = test; PSA = prostate-specific antigen; RCTs = randomized clin- ical trials; NA = not applicable; CT = computed tomography. *—Per U.S. Preventive Services Task Force rating (see Table 3). †—RRR = relative risk reduction: the proportion of deaths from the cancer in question in the control group that could have been prevented by the screening intervention. ‡—NNS = number of patients needed to screen over a 10-year period to prevent one death from the cancer in question. Calculated as the reciprocal of the absolute risk reduction.

promoting new screening tests, it is especially Established screening tests for cancer have an important for family physicians to under- NNS ranging from approximately 500 to stand the various types of bias that can lead 1,100. Although these numbers may initially to an exaggeration of the efficacy of screen- seem discouraging, they indicate that by dili- ing. Physicians must also attend to the gent attention to accepted screening modali- unique ethical dimension of screening, ties, a family physician can be expected to pre- which involves either requiring a high stan- vent several cancer deaths over the course of a dard of evidence of efficacy or, in the absence career. These numbers can also provide a of such evidence, engaging in a process of benchmark by which to evaluate proposed informed consent. new screening programs, as well as providing Table 5 summarizes the current state of the comparisons to screening tests for diseases five most common screening tests for cancer. other than cancer.9

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REFERENCES Study. N Engl J Med 1993;328:1365-71 [Published erratum appears in N Engl J Med 1993;329:672]. 1. Wallace RB. Screening for early and asymptomatic 16. Hardcastle JD, Chamberlain JO, Robinson MH, conditions. In: Wallace RB, ed. Public health and Moss SM, Amar SS, Balfour TW, et al. Randomised preventive medicine. 14th ed. Norwalk: Appleton controlled trial of faecal-occult-blood screening for & Lange, 1998:907-8. colorectal cancer. Lancet 1996;348:1472-7. 2. Marshall KG. Prevention. How much harm? How 17. Kronborg O, Fenger C, Olsen J, Jorgensen OD, much benefit? 4. The ethics of informed consent for Sondergaard O. Randomised study of screening for preventive screening programs. Can Med Assoc J colorectal cancer with faecal-occult-blood test. 1996;155:377-82. Lancet 1996;348:1467-71. 3. Sackett DL, Haynes RB, Guyatt GH, Tugwell P. Early 18. Selby JV, Friedman GD, Quesenberry CP, Weiss NS. diagnosis. In: Sackett DL, Haynes RB, Guyatt GH, A case-control study of screening sigmoidoscopy Tugwell P. Clinical : a basic science for and mortality from colorectal cancer. N Engl J Med clinical medicine. 2d ed. Boston: Little, Brown, 1992;326:653-7. 1991:153-70. 19. Lieberman DA, Weiss DG, Bond JH, Ahnen DJ, 4. Malm HM. Medical screening and the value of Garewal H, Chejfec G. Use of colonoscopy to screen early detection. When unwarranted faith leads to asymptomatic adults for colorectal cancer. N Engl unethical recommendations. Hastings Cent Rep J Med 2000;343:162-8. 1999;29:26-37. 20. Imperiale TF, Wagner DR, Lin CY, Larkin GN, Rogge 5. Doukas DJ, Fetters M, Ruffin MT 4th, McCullough LB. JD, Ransohoff DF. Risk of advanced proximal neo- Ethical considerations in the provision of controversial plasms in asymptomatic adults according to the screening tests. Arch Fam Med 1997;6:486-90. distal colorectal findings. N Engl J Med 2000;343: 6. Marshall KG. Prevention. How much harm? How 169-74. much benefit? 1. Influence of reporting methods 21. Simon JB. Should all people over the age of 50 on perception of benefits. Can Med Assoc J 1996; have regular fecal occult-blood tests? Postpone 154:1493-99. population screening until problems are solved. 7. Wright JC, Weinstein MC. Gains in life expectancy N Engl J Med 1998;338:1151-2,1154-5. from medical interventions—standardizing data on 22. Kerlikowske K, Grady D, Rubin SM, Sandrock C, outcomes. N Engl J Med 1998;339:380-6. Ernster VL. Efficacy of screening mammography. A 8. Rembold CM. Number needed to screen: develop- meta-analysis. JAMA 1995;273:149-54. ment of a statistic for disease screening. BMJ 23. Salzmann P, Kerlikowske K, Phillips K. Cost-effec- 1998;317:307-12. tiveness of extending screening mammography 9. Cook RJ, Sackett DL. The number needed to treat: guidelines to include women 40 to 49 years of age. a clinically useful measure of treatment effect. BMJ Ann Intern Med 1997;127:955-65 [Published erra- 1995;310:452-4 [published erratum appears in tum appears in Ann Intern Med 1998;128:878]. BMJ 1995;310:1056]). 24. Fletcher SW. Whither scientific deliberation in 10. U.S. Preventive Services Task Force. Guide to clini- health policy recommendations? Alice in the won- cal preventive services: report of the U.S. Preventive derland of breast-cancer screening. N Engl J Med Services Task Force. 2d ed. Baltimore: Williams & 1997;336:1180-3. Wilkins, 1996. 25. Elmore JG, Barton MB, Moceri VM, Polk S, Arena 11. Benedet JL, Anderson GH, Matisic JP. A compre- PJ, Fletcher SW. Ten-year risk of false-positive hensive program for cervical cancer detection and screening mammograms and clinical breast exami- management. Am J Obstet Gynecol 1992;166: nations. N Engl J Med 1998;338:1089-96. 1254-9. 26. Gotzsche PC, Olsen O. Is screening for breast can- 12. Frame PS, Frame JS. Determinants of cancer screen- cer with mammography justifiable? Lancet 2000; ing frequency: the example of screening for cervical 355:129-34. cancer. J Am Board Fam Pract 1998;11:87-95. 27. Lefevre ML. Prostate cancer screening: more harm 13. Collins MM, Barry MJ. Controversies in prostate than good? Am Fam Physician 1998;58:432-8. cancer screening. Analogies to the early lung can- 28. Lu-Yao GL, Greenberg ER. Changes in prostate cer screening debate. JAMA 1996;276:1976-9. cancer incidence and treatment in USA. Lancet 14. Henschke CI, McCauley DI, Yankelevitz DF, Naidich 1994;343:251-4. DP, McGuinness G, Miettlinen OS, et al. Early Lung 29. Wingo PA, Ries LA, Rosenberg HM, Miller DS, Cancer Action Project: overall design and findings Edwards BK. Cancer incidence and mortality, 1973- from baseline screening. Lancet 1999;354:99-105. 1995: a report card for the U.S. Cancer 1998;82: 15. Mandel JS, Bond JH, Church TR, Snover DC, 1197-207. Bradley GM, Schuman LM, et al. Reducing mortal- 30. Brawley OW. Prostate carcinoma incidence and ity from colorectal cancer by screening for fecal patient mortality: the effects of screening and early occult blood. Minnesota Colon Cancer Control detection. Cancer 1997;80:1857-63.

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